Gram positive bacterial infections afflict humans around the world. For example, Staphylococcus aureus is a leading pathogen of community and hospital acquired infection of the skin, soft tissues, and other sites (Fridkin et al., N. Engl. J. Med. 352:1436-1444, 2005; Tenover et al., J. Antimicrob. Chemother. 64:441-446, 2009). Compounding the problem is antibiotic resistance, which initially developed in hospitals, but has since spread to the community where rates of methicillin-resistant S. aureus (MRSA) are now approaching those in hospitals (Fridkin et al., N. Engl. J. Med. 352:1436-1444, 2005; Tenover et al., J. Antimicrob. Chemother. 64:441-446, 2009).
The gram positive S. aureus cell wall includes two negatively charged polymers: lipoteichoic acid (LTA) and wall teichoic acid (WTA), which form a highly hydrated polyanionic matrix that is interwoven through the peptidoglycan. While not all gram-positive bacteria have teichoic acid polymers identical to those of S. aureus, alternate polymers generally have functional similarity and anionic character, indicating that anionic polymers are central to the normal function of the gram positive cell wall (Neuhaus et al., Microbiol. Mol. Biol. Rev. 67:686-723, 2003). WTAs are phosphate-rich, carbohydrate-based polymers, which are initially synthesized on a lipid carrier inserted into the inner leaf of the cytoplasmic membrane, before being transported to the cell surface where they are covalently linked to peptidoglycan (Swoboda et al., ChemBioChem 11:35-45, 2010). WTAs affect cation binding, tensile strength, rigidity, and porosity of the gram positive cell wall (Swoboda et al., ChemBioChem 11:35-45, 2010). They are essential for normal S. aureus adherence to epithelial and endothelial cells, and virulence (Suzuki et al., Invest. Ophthalmol. Vis. Sci. 52:3187-3192, 2011; Suzuki et al., Antimicrob. Agents Chemother. 55:767-774, 2011; Weidenmaier et al., Nat. Med. 10:243-245, 2004; Weidenmaier et al., Int. J. Med. Microbiol. 298:515-513, 2008; Weidenmaier et al., Nat. Rev. Microbiol. 6:276-287, 2008; Weidenmaier et al., J. Infect. Dis. 191:1771-1777, 2005).